The aim of this project is to investigate in a nonhuman primate model the biochemical mechanisms that mediate the behavioral and respiratory effects of caffeine and related xanthines. Studies conducted over the last several years in humans and animals have shown that caffeine has many characteristics of typical drugs of abuse including physical dependence, tolerance and self-administration. A valid animal model of caffeine self-administration will allow for the identification of the neurochemical basis of caffeine's reinforcing effects. Accordingly, research efforts during the past year have focused on the development of caffeine self-administration protocols in adult rhesus monkeys. Vascular access ports have provided an effective method to administer caffeine intravenously, and a group of subjects has been trained to perform a task that results in caffeine delivery. Caffeine reliably maintained self-administration behavior over a range of doses in all subjects, demon strating its ability to serve as a reinforcer via the intravenous route. Another group of subjects was provided daily access to caffeine via drinking solutions, and fluid intake was compared to caffeine-free vehicle. All subjects reliably self-administered caffeine via the oral route at doses that were similar to those in the intravenous self-administration protocol. Hence, an effective nonhuman primate model of intravenous and oral caffeine self-administration has been developed to characterize the neuropharmacology of caffeine. Subsequent studies will manipulate pharmacologically specific neurochemical mechanisms, including cyclic nucleotides, in order to identify the neurochemical basis of caffeine reinforcement. Altered sensitivity to drugs with selective mechanisms of action will provide a basis for comparing biochemical and cellular mechanisms that mediate the CNS effects of xanthines and illicit stimulants with high abuse liability.